Accelerated atherosclerosis of the extramural coronary arteries has been considered the major factor underlying cardiac mortality in diabetes mellitus. More recent autopsy data indicate that the incidence and severity of major coronary artery disease in diabetics may not be substantially greater than in nondiabetic subjects. For this reason primary myocardial disease (cardiomyopathy) is receiving increased attention as a major cause of cardiac failure and death in diabetics. We have observed ventricular hypertrophy and degenerative lesions in the myocardium and intramural coronary arteries of the genetically diabetic and obese mouse strain C57BL/ksJ db/db that constitute a cardiomyopathy. The primary event appears to be the autophagocytosis of mitochondria and lipid droplets and their conversion into large residual bodies. Myocardial hypertrophy but not degenerative lesions have been observed in the hearts of mice (C57BL/6J ob/ob) with genetically determined obesity and mild hyperglycemia resembling adult-onset diabetes. It is our working hypothesis that a defect in the lipid metabolism of the severely diabetic db/db mouse results in the degradation of mitochondria and lipids by the lysosomal system and subsequent cardiac degeneration. We propose to test this hypothesis by studying the morphogenesis of the lesions in the db/db mouse by light and electron microscopy, histochemistry and cytochemistry. The results will be compared with similar studies of myocardium from ob/ob mice. Morphometry will be used to quantitate ventricular hypertrophy in both strains of animals. Autoradiography with H3-thymidine will be utilized to establish a labeling index for the endothelial and smooth muscle cells of intramyocardial arteries and the endothelial and perivascular cells of myocardial capillaries and venules. Lanthanum will test the functional integrity of the cardiocytes. The permeability of the myocardial vasculature will be examined using lactoperoxidase and colloidal carbon as probe molecules. We shall also investigate the protective effects on myocardium of dietary restriction and insulin administration.